APPLICANT'S ABSTRACT: Immunosuppression resulting from human immunodeficiency virus (HIV) infection and alcohol abuse are common in the U.S. population and frequently coexist in the same individual. Currently, there is little information on how these two immunosuppressive states might interact with each other to alter host defense mechanisms. Preliminary studies have shown that a number of immune functions are compromised in mice transgenic for the HIV-1 Tat protein. There is also evidence that other HIV-encoded proteins contribute to immunosuppression and immune dysfunctions. It is our hypothesis that alcohol can function as a cofactor with HIV-encoded proteins to further compromise host immune functions and increase host susceptibility to disease progression. This proposal will test this hypothesis in transgenic mice that express Tat (Tat86) protein and HIV mice that express HIV-encoded proteins from a gag-pol defective proviral DNA, and has 3 Specific Aims. Specific Aim 1 to determine the effect of alcohol and HIV proteins on T cell numbers and mechanism of T cell loss. Tat and HIV mice will be exposed to alcohol (20% w/v) in drinking water from 2 to 8 weeks. T cell numbers in thymus and spleen tissues of these animals will be compared to those from alcohol-treated nontransgenic littermates every 2 weeks. Animals in each group without alcohol treatment will serve as controls. We will also focus on expression of cellular factors that are associated with apoptotic mechanisms. Since HIV infection is associated with oxidative stress and Tat itself is known to contribute to it, in Specific Aim 2, we will assess the contribution of alcohol on antioxidant defenses by measuring parameters associated with oxidative stress. In Specific Aim 3, we will compare the immune functions of splenic lymphocytes from alcohol-treated and -untreated mice. Planned experiments will focus on: 1) Cytotoxic T lymphocyte function; 2) Natural killer cell function; and 3) Release of TH1 and TH2 cell-specific cytokines. Information gained from this exploratory project may enhance our understanding of alcohol as a cofactor in HIV pathogenesis and open new avenues of research.